Accepted Manuscript Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer Robert C. Grant , Iris Selander , Ashton A. Connor , Shamini Selvarajah , Ayelet Borgida , Laurent Briollais , Gloria M. Petersen , Jordan Lerner-Ellis , Spring Holter , Steven Gallinger PII: DOI: Reference:
S0016-5085(14)01479-6 10.1053/j.gastro.2014.11.042 YGAST 59485
To appear in: Gastroenterology Accepted Date: 23 November 2014 Please cite this article as: Grant RC, Selander I, Connor AA, Selvarajah S, Borgida A, Briollais L, Petersen GM, Lerner-Ellis J, Holter S, Gallinger S, Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer, Gastroenterology (2015), doi: 10.1053/ j.gastro.2014.11.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
ACCEPTED MANUSCRIPT
Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer
RI PT
Robert C. Grant1,2*, Iris Selander3*, Ashton A. Connor4, Shamini Selvarajah5, Ayelet
Borgida3, Laurent Briollais3, Gloria M. Petersen6, Jordan Lerner-Ellis1,5,7, Spring Holter3,
* Equal contributors.
SC
Steven Gallinger.1,3,4
Ontario Institute for Cancer Research, Canada.
2
Department of Medicine, University of Toronto, Canada.
3
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada.
4
Division of General Surgery, Department of Surgery, University Health Network,
TE D
University of Toronto, Canada.
M AN U
1
5
Laboratory Medicine and Pathobiology, University of Toronto, Canada.
6
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United
Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada.
AC C
7
EP
States of America.
Short title: Germline mutations in pancreatic cancer. Acknowledgements: We thank the Weston Garfield Foundation, Pancreatic Cancer Canada, National Cancer Institute/National Institutes of Health (R01CA97075), the Mount Sinai Hospital Biospecimen Repository, Teresa Bianco, and the patients who participated in this study for supporting this research.
ACCEPTED MANUSCRIPT
Abbreviations: MMR: mismatch repair; NGS: next-generation sequencing; OPCS: Ontario Pancreas Cancer Study; PC: pancreatic cancer; VUS: variants of unknown significance.
RI PT
Correspondence: Steven Gallinger. Division of General Surgery, Toronto General
Hospital. 200 Elizabeth Street, Toronto, ON, Canada. M5G 2C4. Tel: 416 340-4412. Fax: 416 340-3808. Email: [email protected]
SC
Disclosures: None. Author contributions:
M AN U
Study concept and design: R.C.G., L.B., J.L.E., S.H., S.G.
Acquisition of data: R.C.G., I.S., A.A.C., S.S., A.B., L.B., G.M.P., J.L.E., S.H., S.G. Analysis and interpretation of data: R.C.G., I.S., A.A.C., S.S., A.B., L.B., G.M.P., J.L.E., S.H., S.G.
TE D
Drafting of the manuscript: R.C.G., S.G.
Critical revision of the manuscript for important intellectual content: R.C.G., I.S., A.A.C., S.S., A.B., L.B., G.M.P., J.L.E., S.H., S.G.
AC C
EP
Obtained funding: G.M.P., J.L.E., S.G.
1
ACCEPTED MANUSCRIPT
Abstract: Background & Aims: We investigated the prevalence of germline mutations in APC,
and TP53 in patients with pancreatic cancer.
RI PT
ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11,
Methods: The Ontario Pancreas Cancer Study enrolls consenting participants with
pancreatic cancer from a province-wide electronic pathology database; 708 probands
SC
were enrolled from April 2003 through August 2012. To improve precision of BRCA2 prevalence estimates, 290 probands were randomly selected from 3 strata, based on
M AN U
family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort. Results: Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in
TE D
BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%−5.6%). Carrier status was significantly associated with breast cancer in the proband or first-degree relative (P
S0016-5085(14)01479-6 10.1053/j.gastro.2014.11.042 YGAST 59485
To appear in: Gastroenterology Accepted Date: 23 November 2014 Please cite this article as: Grant RC, Selander I, Connor AA, Selvarajah S, Borgida A, Briollais L, Petersen GM, Lerner-Ellis J, Holter S, Gallinger S, Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer, Gastroenterology (2015), doi: 10.1053/ j.gastro.2014.11.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
ACCEPTED MANUSCRIPT
Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer
RI PT
Robert C. Grant1,2*, Iris Selander3*, Ashton A. Connor4, Shamini Selvarajah5, Ayelet
Borgida3, Laurent Briollais3, Gloria M. Petersen6, Jordan Lerner-Ellis1,5,7, Spring Holter3,
* Equal contributors.
SC
Steven Gallinger.1,3,4
Ontario Institute for Cancer Research, Canada.
2
Department of Medicine, University of Toronto, Canada.
3
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada.
4
Division of General Surgery, Department of Surgery, University Health Network,
TE D
University of Toronto, Canada.
M AN U
1
5
Laboratory Medicine and Pathobiology, University of Toronto, Canada.
6
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United
Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada.
AC C
7
EP
States of America.
Short title: Germline mutations in pancreatic cancer. Acknowledgements: We thank the Weston Garfield Foundation, Pancreatic Cancer Canada, National Cancer Institute/National Institutes of Health (R01CA97075), the Mount Sinai Hospital Biospecimen Repository, Teresa Bianco, and the patients who participated in this study for supporting this research.
ACCEPTED MANUSCRIPT
Abbreviations: MMR: mismatch repair; NGS: next-generation sequencing; OPCS: Ontario Pancreas Cancer Study; PC: pancreatic cancer; VUS: variants of unknown significance.
RI PT
Correspondence: Steven Gallinger. Division of General Surgery, Toronto General
Hospital. 200 Elizabeth Street, Toronto, ON, Canada. M5G 2C4. Tel: 416 340-4412. Fax: 416 340-3808. Email: [email protected]
SC
Disclosures: None. Author contributions:
M AN U
Study concept and design: R.C.G., L.B., J.L.E., S.H., S.G.
Acquisition of data: R.C.G., I.S., A.A.C., S.S., A.B., L.B., G.M.P., J.L.E., S.H., S.G. Analysis and interpretation of data: R.C.G., I.S., A.A.C., S.S., A.B., L.B., G.M.P., J.L.E., S.H., S.G.
TE D
Drafting of the manuscript: R.C.G., S.G.
Critical revision of the manuscript for important intellectual content: R.C.G., I.S., A.A.C., S.S., A.B., L.B., G.M.P., J.L.E., S.H., S.G.
AC C
EP
Obtained funding: G.M.P., J.L.E., S.G.
1
ACCEPTED MANUSCRIPT
Abstract: Background & Aims: We investigated the prevalence of germline mutations in APC,
and TP53 in patients with pancreatic cancer.
RI PT
ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11,
Methods: The Ontario Pancreas Cancer Study enrolls consenting participants with
pancreatic cancer from a province-wide electronic pathology database; 708 probands
SC
were enrolled from April 2003 through August 2012. To improve precision of BRCA2 prevalence estimates, 290 probands were randomly selected from 3 strata, based on
M AN U
family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort. Results: Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in
TE D
BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%−5.6%). Carrier status was significantly associated with breast cancer in the proband or first-degree relative (P
